Control of neurotransmitter receptor function may occur by a previously undescribed mechanism: serine protease cleavage. Preliminary data show that thrombin can cleave the NMDA receptor NR1 subunit in transfected cells and brain homogenates. Interestingly, mRNA for the precursor to thrombin is found widely distributed in the developing and adult brain. Pathologies associated with disruptions in the blood-brain barrier cause an elevation in the concentration of thrombin in cerebrospinal fluid. Both the NMDA receptor and thrombin are implicated in brain damage associated with several pathologies, including stroke, head trauma, and Alzheimer's Disease. The interaction of these two proteins may exacerbate disease states. The goal of this project is to define the physiological consequences of thrombin proteolysis of the NR1 subunit of the NMDA receptor. Toward this end, experiments are designed (a) to examine the effects of thrombin proteolysis of the NMDA receptor on receptor function, localization and turnover; (b) to define the thrombin-sensitive site of the NR1 subunit; (c) to find whether thrombin sensitivity is unique to the NR1 subunit in the glutamate receptor family; and (d) to determine if thrombin proteolysis affects NMDA receptor-mediated neurotoxicity. This research project has the potential to uncover a novel mechanism for control of NMDA receptor function during a variety of brain pathologies, and may suggest new strategies for developing better treatments for these diseases.